SUMMARY. This is a multi-PI application for the U24 Cooperative Agreement to develop a state-of-the-art Alzheimer Clinical Trial Consortium (ACTC) to support the conduct of academic clinical trials across the continuum of Alzheimer's disease (AD). This ACTC will leverage the depth and breadth of AD clinical research teams at USC, Harvard, and the Mayo Clinic, as well as the considerable experience of investigators at 35 expert AD trial sites. We aim to create an optimized infrastructure to more efficiently launch, rapidly recruit, improve the diversity, and successfully complete NIH supported clinical trials in AD and related dementias. We will utilize streamlined contracting processes, a centralized IRB with a specific focus on neurodegenerative diseases, and incorporate state-of-the-art informatics and statistical analyses. We propose to redouble our efforts to improve the diversity of participants in AD clinical trials, incorporating learnings from our recent experience, and establishing a new Minority Outreach and Recruitment (MORE) Team to support both central and local partnerships with communities of color. We will foster continued innovation in AD trial design, providing expertise on novel cognitive, imaging, and biomarker outcomes to support future ACTC trial applications. We will evaluate promising exploratory measures imbedded in our current trials, such as Tau PET imaging and computerized cognitive testing, and work to incorporate these measures into a robust platform for future Proof of Concept (POC) trials to rapidly assess signals of efficacy. We propose a tightly coordinated, distributed leadership model to create a true consortium and take full advantage of the expertise across multiple institutions. The ACTC Coordinating Center will leverage the highly experienced teams in Clinical Operations, Data Systems and Management, and Biostatistics at USC. The MRI Unit, led by Mayo, and PET Unit, led by Harvard and UC Berkeley, will capitalize on unparalleled experience with multi-site protocols through ADNI, the A4 Study, and multiple ongoing clinical trials. The Clinical Outcome Instrument and Biomarkers Units will leverage world-class expertise from Mayo, Harvard, and USC to incorporate both standard and novel outcome measures in future trial designs. This ACTC will provide expertise and infrastructure to design and conduct trials across the full continuum of AD, from primary prevention initiatives to combination trials for advanced symptomatic stages. We also stand ready to collaborate on trials in other age- related dementias, leveraging the experience of the NeuroNext team at Harvard and other expert investigators in vascular and non-AD neurodegenerative diseases. We will build on our successes with public/private partnerships and continue to strengthen our strategic alliances to conduct large scale trials, but will also focus on supporting novel approaches to smaller investigator-initiated POC studies that will better inform Phase 3 decision-making. Finally, we will provide training and leadership opportunities to young clinical investigators to facilitate continued innovation in trial design, and catalyze the next generation of AD clinical trials.